Despite recent advances in the dental biomaterials field, metal implant corrosion remains a pertinent clinical issue. Implanted metals are subject to wear and corrosion due to mechanical and environmental factors. This degradative process releases metal ions, which stimulate fibrous tissue formation, leading to impairment of osseointegration and implant failure. Titanium and titanium alloy, metals used for dental applications, release ions which localize to tissues surrounding implants. Although it is well established that metal ions impair osteogenesis, the molecular mechanisms by which metal ions direct tissue differentiation have yet to be identified. Transforming growth factor beta (TGF-[unreadable]) is a key factor driving fibrotic responses and impedes osteoblast differentiation. Thus, we hypothesize that TGF-?[unreadable] is an important mediator for the effects of metal ions on tissue differentiation at the tissue-implant interface. TGF-?[unreadable] must be activated from its biologically latent form to induce fibrogenesis. Activation of latent TGF-(3 occurs by multiple mechanisms, including oxidative modification of the latent complex and binding to thrombospondin-1 (TSP1), a matricellular glycoprotein present in wounds and in fibrous tissue. Bone marrow-derived mesenchymal stem cells (MSCs) are pluripotent, home to sites of tissue injury, and play a role in both normal and fibrotic repair responses. Although MSCs have been studied extensively in other disease processes, the role of stem cells and the mechanisms regulating repair and fibrosis in response to implant metals are poorly understood. In preliminary studies, we tested the hypothesis that TSP1-dependent TGF-?[unreadable] activation is important for fibrotic responses to titanium and stainless steel ions. Cocktails of metal ions were used to mimic the composition of titanium, titanium alloy and stainless steel corrosion products in vitro. MSCs treated with metal ions showed increased levels of TGF-?[unreadable] activity and expression of myofibroblast markers, partially due to TSP1-dependent TGF-?[unreadable] activation, and inhibition of osteogenesis. These studies support the hypothesis that titanium and titanium alloy corrosion products alter tissue integration of metal implants by stimulating TGF-?[unreadable] -dependent myofibroblastic differentiation of stem cells, leading to fibrous tissue formation surrounding the implant. This study will specifically determine the mechanisms by which metal corrosion products induce the myofibroblast phenotype by assessing the involvement of TSP1 and oxidative mechanisms of TGF-?[unreadable] activation in both in vitro and in vivo systems. The goal of this study is to improve implant biocompatibility with host tissue by elucidating the role of mesenchymal stem cells in TGF-?[unreadable] dependent fibrous tissue formation. [unreadable] [unreadable] [unreadable]